title: MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers.
abstract: Chromosomal translocations are critically involved in the molecular pathogenesis of B-cell lymphomas, and highly recurrent and specific rearrangements have defined distinct molecular subtypes linked to unique clinicopathological features. In contrast, several well-characterized lymphoma entities still lack disease-defining translocation events. To identify novel fusion transcripts resulting from translocations, we investigated two Hodgkin lymphoma cell lines by whole-transcriptome paired-end sequencing (RNA-seq). Here we show a highly expressed gene fusion involving the major histocompatibility complex (MHC) class II transactivator CIITA (MHC2TA) in KM-H2 cells. In a subsequent evaluation of 263 B-cell lymphomas, we also demonstrate that genomic CIITA breaks are highly recurrent in primary mediastinal B-cell lymphoma (38%) and classical Hodgkin lymphoma (cHL) (15%). Furthermore, we find that CIITA is a promiscuous partner of various in-frame gene fusions, and we report that CIITA gene alterations impact survival in primary mediastinal B-cell lymphoma (PMBCL). As functional consequences of CIITA gene fusions, we identify downregulation of surface HLA class II expression and overexpression of ligands of the receptor molecule programmed cell death 1 (CD274/PDL1 and CD273/PDL2). These receptor-ligand interactions have been shown to impact anti-tumour immune responses in several cancers, whereas decreased MHC class II expression has been linked to reduced tumour cell immunogenicity. Thus, our findings suggest that recurrent rearrangements of CIITA may represent a novel genetic mechanism underlying tumour-microenvironment interactions across a spectrum of lymphoid cancers.
authors.affiliation: Department of Pathology and Laboratory Medicine, Centre for Lymphoid Cancers and the Centre for Translational and Applied Genomics, Vancouver, British Columbia, V5Z4E6, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Woolcock
authors.forename: Lixin
authors.initials: L
authors.lastname: Rui
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kawahara
authors.forename: Pedro
authors.initials: P
authors.lastname: Farinha
authors.forename: Nathalie A
authors.initials: NA
authors.lastname: Johnson
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Adele
authors.initials: A
authors.lastname: Telenius
authors.forename: Susana Ben
authors.initials: SB
authors.lastname: Neriah
authors.forename: Andrew
authors.initials: A
authors.lastname: McPherson
authors.forename: Barbara
authors.initials: B
authors.lastname: Meissner
authors.forename: Ujunwa C
authors.initials: UC
authors.lastname: Okoye
authors.forename: Arjan
authors.initials: A
authors.lastname: Diepstra
authors.forename: Anke
authors.initials: A
authors.lastname: van den Berg
authors.forename: Mark
authors.initials: M
authors.lastname: Sun
authors.forename: Gillian
authors.initials: G
authors.lastname: Leung
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Jones
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Savage
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Rimsza
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Horsman
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steidl
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D060890:B7-H1 Antigen; D001483:Base Sequence; D045744:Cell Line, Tumor; D056905:Chromosome Breakpoints; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000235:genetics*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D061027:Programmed Cell Death 1 Ligand 2 Protein; D012334:RNA, Neoplasm / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D046888:Tissue Array Analysis; D015534:Trans-Activators / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*; D059016:Tumor Microenvironment
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D012334:RNA, Neoplasm; D015534:Trans-Activators